She knockout (KO) mice have multiple features of healthy aging, including reduced adiposity, resistance to high-fat diets, stress resistance, and increased stem cell renewal capacity. She mice have increased median longevity on a calorie-restricted diet, and have increased survival on high-fat diets in a pilot study. There are multiple metabolic similarities observed in common among ShcKO and CR mice: reduced insulin levels, decreased glucose levels, increased insulin sensitivity, decreased oxidation of carbohydrates, and increased oxidation of lipids and proteins. Thus we have multiple goals in Project 2: 1) to identify the mechanism(s) by which ShcKO mice resist adiposity and stress, 2) to understand the mechanism by which She depletion extends median lifespan on CR, and 3) to identify She-inhibitory drugs that could be used to improve insulin signaling and healthy aging. Impact and Significance. The research will have substantial impact. First, we as Westerners live in a high fat environment, and| obesity and diabetes and their consequent co morbidities of stroke and cardiovascular disease are a massive health problem for aging Americans. Thus, identifying anti-adiposity mechanisms in She mice could have important implications reducing adiposity and extending health span in humans. Second, longevity-inducing mutations in the insulin/lgf-1 pathway and CR appear to share some similarities of mechanism, and CR inhibits Shcs. Thus we suspect that CR and She mechanisms at least partially overlap, which is supported by the increased median lifespan of ShcKO mice on CR. Third, She mutant mice and their cells are resistant to multiple stressors and appear to have altered autophagy and increased stem cell regeneration, which could have benefit in understanding the mechanisms of age-related stress resistance. Finally, screening has the potential to identify novel She-inhibitory drugs to translate the healthy aging of ShcKO mice to humans. Thus we plan to have an impact on the mechanisms for resistance to adiposity and diabetes, and the identification of small molecules and diets that promote healthy aging in humans.